Ovarian cancer is a cancer with a low incidence, compared with breast cancer or uterine cancer, among gynecologic cancers. Both incidence and mortality of this cancer, however, have been on the increase in recent years. In general, ovarian cancer is substantially asymptomatic early in the course of the disease and often found at the already advanced stage of symptoms. Hence, this disease has poor prognosis and exhibits the highest mortality among gynecologic cancers. Ovarian cancer is known to include, for example, surface epithelial-stromal tumors (hereinafter, referred to as “epithelial ovarian cancer”) developed from surface epithelial cells in the ovary and germ cell tumors developed from germ cells, depending on the area affected. Of them, epithelial ovarian cancer accounts for approximately 90% of all ovarian cancer cases and is often seen particularly in middle-aged women in their 40s or older. Thus, the early detection of epithelial ovarian cancer is important for the treatment of the disease.
The ovary is an organ that has no contact with the outside of the body. Unlike the uterus, the ovary can be neither examined endoscopically nor subjected to cell harvest without abdominal section or perforation. In addition, epithelial ovarian cancer is generally difficult to detect by palpation before the ovary is enlarged at the advanced stage of symptoms. Hence, epithelial ovarian cancer is often undetected in ordinary examination or diagnosis methods. Although echography, MRI, CT, or the like is relatively effective for the early detection of epithelial ovarian cancer, this examination itself is extensive work with a high cost. In addition, these approaches, unfortunately, do not always have high diagnostic accuracy to distinguish between benign and malignant tumors.
Against this backdrop, tumor markers have received attention in recent years. The tumor markers refer to substances that are produced by cancer cells or produced by cells surrounding cancer cells in response to the cancer cells. The abundance of each tumor marker in a body fluid can reflect the presence or absence of tumor or the prognosis thereof and therefore serve as an index for, for example, cancer diagnosis and decision on therapeutic strategies. Also, this approach permits examination using a body fluid and is thus relatively low invasive. Advantageously, this examination is also convenient and low in cost.
Tumor markers composed of proteins such as CA125, CA602, CA130, CA72-4, CA546, CA 19-9, and STN have been known so far as tumor markers for epithelial ovarian cancer (Non Patent Literatures 1 to 6). Methods for diagnosis of cancer using these tumor markers typically involve measuring the expression levels of the tumor markers in the serum of normal individuals and epithelial ovarian cancer patients and determining the presence or absence of cancer developed in a test subject on the basis of the difference in the levels.
These proteins, however, present specificity problems in such a way that CA125 exhibits positivity to a non-cancer benign gynecologic disease such as endometriosis or CA72-4, CA19-9, and STN exhibit positivity to various cancers of the digestive system including the stomach and the large intestine in addition to ovarian cancer. Epithelial ovarian cancer is further classified into serous, clear cell, mucinous, and endometrioid tumors depending on the histological type. The markers differ in reactivity among these histological types and therefore, do not correctly reflect the progression of cancer in some cases. For example, the ovarian cancer markers such as CA125, CA602, and CA546 have a low positive rate for mucinous ovarian cancer. Unfortunately, this histological type is therefore rarely detected even at the advanced stage.
Patent Literature 1 discloses a monoclonal antibody for use in the diagnosis of cancers including ovarian cancer against human galactosyltransferase associated with tumor (GAT) as a tumor marker, a hybridoma producing the antibody, and a method for assaying human galactosyltransferase associated with tumor in a specimen using the antibody. Also, Patent Literature 2 discloses a method for detecting gynecologic cancers early using glycosyltransferases β1,3-galactosyltransferase 5, β1,3-galactosyltransferase 4, and N-acetylglucosamine-6-O-sulfotransferase 2 as tumor markers. These glycosyltransferases used as tumor markers in Patent Literatures 1 and 2 are enzymes that synthesize sugar chains to be bound with, for example, glycoproteins, glycolipids or proteoglycans, and are usually anchored on Golgi membranes as membrane proteins localized to the Golgi bodies. Thus, these enzymes are not secreted to the outside of the cells and are therefore rarely detected in the body fluids of normal individuals. In ovarian cancer, however, it is known that glycosyltransferases are abnormally cleaved due to the increased expression level of a certain kind of protease and released to the outside of the cells. As a result, significant amounts of glycosyltransferase fragments are detected in body fluids.
The glycosyltransferase β1,4-galactosyltransferase described in Patent Literature 1 has an exceedingly high expression level among glycosyltransferases and is thus secreted in large amounts to the outside of the cell. Hence, this glycosyltransferase exhibits a serum concentration of approximately 200 ng/mL even in normal individuals and thus fails to distinguish between benign disease and cancer by its enzymatic activity alone. Accordingly, Patent Literature 1 was focused on the presence of a fragment of the abnormally cleaved glycosyltransferase in the culture supernatant of ovarian cancer cells and the ascitic fluid of an ovarian cancer patient. An antibody that recognizes only this fragment was used to attempt the construction of an assay system highly specific for ovarian cancer. Nonetheless, a commercially available clinical diagnosis kit based on this assay system exhibited positivity even for healthy women in some cases (Non Patent Literature 7). For this reason, GAT is currently used mainly in the monitoring of ovarian cancer recurrence and rarely used as a marker for early detection.
In Patent Literature 2, an attempt was made to detect marker candidate proteins in the blood of gynecologic cancer patients on the basis of reports stating that the expression of various proteins including glycosyltransferases is generally increased or decreased in cancer tissues. As a result, two glycosyltransferases were found to be useful in assay. The literature discloses an assay method according to the findings. In this case, however, the expression or synthesis products of these glycosyltransferases are reportedly related to digestive system cancers rather than gynecologic cancers. Although their expression was then confirmed in ovarian cancer cell lines (Non Patent Literature 8), there has been no report on the comparison of the expression levels between ovarian cancer or other gynecologic cancers and digestive system cancers.
As mentioned above, Patent Literatures 1 and 2 are directed only to the detection of markers in the body fluids of ovarian cancer patients with little consideration given to glycosyltransferase expression in ovarian cancer and disclose a glycosyltransferase fragment that happened to be measurable, as an ovarian cancer marker. This may lead to specificity problems as ovarian cancer markers.